We previously reported that interleukin (IL)-4 protects against susceptibility of mice to acetaminophen-induced liver injury (AILI), the leading cause of acute liver failure. The hepatoprotective effect of IL-4 was due at least in part to its induction of gamma-glutamylcysteine ligase (gamma-GCL), the rate determining enzyme in glutathione (GSH) synthesis, as IL-4 deficiency resulted in decreased mRNA and protein levels of gamma-GCL, prolonged depletion of GSH levels in the liver, and increased susceptibility to AILI. Moreover, the prolonged diminished levels of hepatic GSH seen in acetaminophen-treated IL-4 deficient mice contributed to the severity of AILI at least in part by causing continuous hepatic oxidative stress and resultant sustained activation of c-Jun-N-terminal kinase (JNK) signaling and mitochondrial dysfunction. In contrast to these findings, this year we found that IL-4 enhanced the severity of halothane-induced liver injury in mice by a mechanism that involved the hepatic infiltration of eosinophils. Conclusion: This year we showed that IL-4 can have either a hepatoprotective or hepatoprotoxicant role in DILD that appears to be dependent on the mechanism of DILD. When IL-4 enhances DILD, its mechanism of toxicity may involve the activation and hepatic infiltration of eosinophils, which have long been associated with many cases of DILD without a known function until now. Our findings have clinical implications as polymorphisms in the IL-4 and/or IL-4 receptor genes have been associated with enhanced susceptibility to DILD.